Whole erythrocyte cells, ghosts, and extracted proteins will be studied using differential scanning calorimetry, thermal gel analysis, CD, EPR, NMR and volumetric methods. Primary emphasis will be given to calorimetry and thermal gel analysis. The erythrocyte membrane undergoes three cooperative structural transitions in the temperature range 45 degrees to 65 degrees C., with a smaller fourth transition at 77 degrees at PH 7.4, 77 imosm. These transitions are highly reproducible and are most readily seen in the calorimeter, where dilute suspensions can be examined. They are irreversible and associated at least partially with protein unfolding, although changes in the lipid phase and changes in protein quaternary structure may occur concomitantly with unfolding in at least two of the major transitions. Partial identification of the specific proteins involved in these transitions has been achieved by using solubilization methods and partial proteolysis. A large number of protein participants are involved in at last two of these transitions. One of these latter two can be turned on and off reversibly by small variations in salt concentration in the physiological range, and the possibility of relationship of this to transport control will be investigated. It has also been shown that spectrin and component III each possess at least two independent structural regions, and methods have been devised to study these individually. The structural subregions of spectrin have been shown to strongly resemble the subregions of muscle myosin, raising anew the possibility of analogy between this membrane protein and the contractile protein. A new method has been developed (thermal gel analysis) which allows one to observe structural changes for each individual protein on the membrane. The great potential of the method has been demonstrated with the erythrocyte membrane, where it has told us which specific proteins are involved in each of the thermal transitions. The thermal gel method shows promise for detecting subtle differences btween the protein components of normal and pathological membranes, such as are thought to occur in some blood diseases and in various forms of cancer.